The compound gossypol is a polyphenolic triterpene having the formula: ##STR2## wherein b and c are tautomers of the aldehyde a. Gossypol exists primarily as the aldehyde form in nonpolar solvents and is represented as such throughout the specification and claims.
The substance is found in certain types of cotton plants, and is the main toxic material found therein. As such, it has limited the use of cottonseed meal as a source of dietary protein for monogastric animals including man. Gossypol has, however, exhibited a number of useful biological properties which have aroused great interest in the compound among medical researchers.
For example, gossypol has been under investigation in China, based on the discovery that the use of cottonseed oil in cooking induced infertility in men (Nat'l. Coordinating Groups on Male Fertility, Chinese Med. J. 4: 417-428, 1978). This feature of its activity has been used to attempt to produce a male contraceptive using gossypol as the active agent (U.S. Pat. No. 4,381,298) and also a vaginal spermicide (U.S. Pat. No. 4,297,341). Similar properties have been attributed to the compound hemigossypol. (Manmade, et al., Experiencia 39, 1276). It has further been shown to have antiviral properties, being capable of inactivating parainfluenza, type 3 and herpes simplex viruses (Dorsett et al., J. Pharm. Sci. 64, 1073, 1975). Antiparasitic activity has also been found to be associated with gossypol. Growth of both Trypanosoma cruzi (Montamat et al., Science 218, 218, 1982) and Plasmodium falciparum (Heidrich et al., IRCS Med. Sci. 11, 304, 1983) is known to be inhibited by gossypol Overall, however, the practical application of these important properties has been prevented by the toxicity and unpleasant side effects produced by gossypol.
A considerable body of research indicates that the toxicity of gossypol is related to the reactions of the aldehyde groups on the molecule. It should thus be theoretically possible to remove the aldehyde groups from a gossypol molecule and reduce the toxicity. However, it is unclear at present how much of gossypol's biological activity is also tied to the presence of the reactive aldehyde groups. Therefore, it is impossible to know in advance whether the gossypol molecule without the aldehydes would exhibit the same activity as the natural molecules. It is also completely unpredictable as to what, if any, substituent groups might be used as an appropriate replacement for the aldehyde groups, and which might aid in allowing the new compound to mimic the biological activity of the original compound.
It has now been unexpectedly discovered that a new class of compounds, derived from gossypol, or hemigossypol, succeed in retaining a similar, and sometimes higher, level of activity than the parent compound, while being free of the toxic aldehyde groups. Such compounds are shown herein, like gossypol itself, to exhibit significant levels of biological activity with significantly reduced toxicity. Further, an additional new class of compounds has been prepared which serve as useful intermediates in the preparation of the biologically active compounds of the present invention.